Methods and Patients
This case series was evaluated but the Institutional Review Board (IRB) at Children’s Minnesota and deemed exempt from review. Each patient clinical course is summarized in Table 1. Full details of each of the patient is described at length in Supplemental File 1.
Patient 1 is a 15-year-old male who has experienced 5 reactivations of LCH. He presented with left mastoid LCH at 3.5 years of age, confirmed by biopsy with CD1a and S-100 positivity. Reactivations of LCH included the pituitary stalk, mastoid and bone lesions. He was treated with multiple regimens of chemotherapy (Supplemental File 1). Systemic involvement at age 14 included bones, lungs, abdominal lymph nodes, pancreas and perianal area. A course of cladribine, cytarabine and clofarabine resulted in a complete response by PET/CT that was complicated by prolonged bone-marrow suppression. NGS on the last biopsy showed BRAF p.N486_P490 deletion (Fig. 1.A). He was treated with trametinib 0.5 - 1 mg daily (0.008 - 0.016 mg/kg) and remains with no active disease on this dose at 18 months follow-up with intermittent grade 1 skin rash and grade 3 CPK elevation (Table 1).
Patient 2 is 22-year-old male with LCH and 2 reactivations. He was diagnosed at age 18 years with LCH involving lungs, skin and diabetes insipidus. Lung and skin biopsies confirmed LCH with CD1a and S100 positivity. He was treated with cytarabine, but skin reactivation required hydroxyurea and methotrexate. He then had a second reactivation of pulmonary LCH. No biopsy was done but NGS of a prior sample revealedBRAF p.N486_P490 deletion (Fig 1.A). Therapy with trametinib 2 mg daily (0.016mg/kg) produced a partial response with residual extensive cystic and nodular lung disease. He continues on monotherapy with trametinib 2 mg daily with stable lung disease after 12 months of therapy. Toxicity has been grade 2 skin rash and grade 4 CPK elevation, but dose level remains unchanged (Table 1).
Patient 3 is a 2-year-old male with multisystem LCH diagnosed at 2 weeks of age when skin biopsy demonstrated CD1a and CD207 positivity. At 2 months of age he had systemic disease including bones, liver, pancreas and lungs. NGS from the skin biopsy revealed a low level of MAP2K1 p.K57_G61del (Fig 1.B). He received a short corticosteroid pulse and trametinib 0.125 mg (0.030 mg/kg) daily was started in parallel with prednisolone. His lesions rapidly responded and he continues on trametinib monotherapy 0.25 mg daily (0.019 mg/kg/day) with no active disease after 22 months of therapy. Toxicity has been a grade 1 skin rash and grade 1 CPK elevation (Table 1).